Colonic K⁺ secretion occurs via the pump-leak mechanism, where K⁺ is taken up basolaterally in the colonic crypt epithelial cell and leaves the cytosol via apical K⁺ channels. The large conductance, Ca²⁺-activated K⁺ channel (BK, K_Ca1.1) has been identified as the relevant apical channel involved in K⁺ secretion in the mammalian distal colon. The BK channel is composed of 4 α-subunits (KCNMA1) and 4 modulatory β-subunits, of which there are 4 isoforms (KCNMB1-4). The channel is primarily activated by membrane depolarization and increases in [Ca²⁺]_i, the sensitivity and kinetics depend on the associated β-subunits. In the murine colon, only the β₂-subunit (KCNMB2) is expressed. The β₂-subunit increases the sensitivity of the BK channel to [Ca²⁺]_i, thus facilitating channel opening. However, the β₂-subunit also facilitates fast inactivation of the channel via a ball-and-chain inactivation mechanism.

We have acquired a global KCNMB2 knockout mouse, and are currently characterizing the colonic K⁺ excretion in this mouse. Surprisingly, we found that on a standard diet, KCNMB2^-/- mice have a tentatively increased colonic K⁺ secretion. Feeding a 5% KCl diet for 4 days markedly elevates colonic K⁺ secretion. Under these conditions, we identify that KCNMB2^-/- mice display a greatly increased colonic K⁺ secretion as compared to wild type controls. Similarly, apical P2Y receptor stimulation caused a greater K⁺ secretory response in the KCNMB2^-/- as compared to the WT. Taken together, these results define a gain of function of colonic K⁺ secretion in the KCNMB2^-/- mouse.